This randomized, double blind, placebo controlled trial will evaluate the impact of adding everolimus to the combination of weekly paclitaxel plus bevacizumab in the first-line treatment of women with HER2-negative metastatic breast cancer. Patients will be randomized (1:1) to receive either paclitaxel/bevacizumab/everolimus (Treatment Arm 1) or paclitaxel/ bevacizumab/placebo (Treatment Arm 2). Patients will be evaluated for response to treatment every 8 weeks; responding and/or stable patients will continue treatment, with re-evaluations every 8 weeks, until tumor progression or

intolerable toxicity occurs. Outcomes will be assessed for each treatment arm

separately. This trial is not intended to compare treatment arms primarily. Any such analyses are exploratory and will be conducted without adjustment for multiple hypothesis testing.

Progression-free survival will be measured from Day 1 of study drug administration to disease progression defined by Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Secondary Outcome Measures:

Number of Patients With Treatment-related Adverse Events (AEs) as a Measure of Safety and Tolerability [ Time Frame: every 4 weeks until intolerable toxicity occurs ] [ Designated as safety issue: Yes ]

Assessments will be made based on the analysis of reported incidence of treatment-emergent AEs

Defined as time between date of objective response and date of response to disease progression or death, as defined by RECIST v1.1 criteria. Objective response is defined as either complete response [CR] or partial response [PR]. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

International normalized ratio (INR) <=1.5 or prothrombin time (PT)/partial

thromboplastin time (PTT) within normal limits (WNL) of the institution (if patient is not on anti-coagulation therapy). Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin are eligible if the INR is stable and within the therapeutic range prior to study treatment initiation.

Adequate lipid profile: total cholesterol <=300 mg/dL OR <=7.75 mmol/L and fasting triglyceride 2.5 x ULN. Note: In case one or both of these thresholds are exceeded,the patient can only be included after initiation of appropriate lipid lowering medication.

Patients with proteinuria at screening as demonstrated by either:

· Urine protein creatinine (UPC) ration >1.0 at screening

or

Urine dipstick for proteinuria >=2+ (patients discovered to have

>=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour

urine collection and must demonstrate <1 g of protein in 24 hours to be

Patients with previous history of invasive cancers (including breast cancer) are eligible if definitive treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease.

Patient must be accessible for treatment and follow-up.

All patients must be able to understand the investigational nature of the study and give written informed consent prior to study entry.

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Exclusion Criteria:

Patients with active brain metastases or meningeal metastases. Patients who have had brain metastases resected, or have received brain radiation therapy >4 weeks prior to study entry are eligible, if they meet all of the following criteria: 1) residual symptoms < grade 2, 2) no dexamethasone requirement, and 3) follow-up MRI shows regression of lesions after treatment and no new lesions appearing.

Patients who are current receiving systemic cancer therapy or have received

previous systemic therapy within 4 weeks of the start of study drug (e.g.

chemotherapy, antibody therapy, targeted agents).

Women who are pregnant or lactating. All patients with reproductive potential must agree to use effective contraception from time of study entry until at least 3 months after the last administration of study drug.

History of stroke or transient ischemic attack within 6 months prior to first

bevacizumab dose.

Patients with any non-healing wound, ulcer, or long-bone fracture.

Patients with clinical history of hemoptysis or hematemesis.

Patients with any history of a bleeding diathesis or coagulopathy.

Patients with a PEG or G tube cannot be enrolled into this trial.

History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to beginning bevacizumab.

Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

Patients who have any severe and/or uncontrolled medical conditions or other

conditions that could affect their participation such as:

severe impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air

uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.

History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that might affect interpretation of the results of this study, or render the subject at high risk for treatment complications.

History of hypersensitivity to Cremophor EL (polyoxyethylated castor oil) or a drug formulated in Cremophor EL, such as paclitaxel.

Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or its excipients.

Patients with a known HIV seropositivity.

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Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00915603